Method for spectrophotometric blood oxygenation monitoring of organs in the body

ABSTRACT

A method and apparatus for non-invasively determining a blood oxygen saturation level within tissue of an internal organ is provided. The method includes: applying a near infrared spectrophotometric sensor on an external surface of an organ; operating the sensor to emit light from a light source directly into the tissue of the organ at a first tissue location, and to sense the emitted light at a second tissue location, which emitted light has traveled through the tissue between the first and second tissue locations, and to produce signals representative of the intensity of the sensed emitted light; using a processor to execute instructions, which instructions cause the processor to: determine an attenuation value of the emitted light for each wavelength, and determine a blood oxygen saturation level of the organ tissue using the determined attenuation values for each of the plurality of wavelengths.

This application is a continuation of U.S. patent application Ser. No.15/172,992 filed Jun. 3, 2016, which is a divisional of U.S. patentapplication Ser. No. 13/511,928, now U.S. Pat. No. 9,364,175, filed Oct.4, 2012, which is a national stage application of PCT Patent ApplicationNo. PCT/US2010/058059 filed on Nov. 24, 2010, which claims priority toU.S. Provisional Patent Application No. 61/264,080 filed Nov. 24, 2009,the disclosures of which are herein incorporated by reference.

BACKGROUND OF THE INVENTION 1. Technical Field

This invention relates to methods for non-invasively determiningbiological tissue oxygenation in general, and to non-invasive methodsutilizing near-infrared spectroscopy (NIRS) techniques in particular.

2. Background Information

Oxygen saturation in a mammalian subject can be defined as:

$\begin{matrix}{{\text{O}_{2}\mspace{14mu} {saturation}\mspace{14mu} \%} = {\frac{{HbO}_{2}}{\left( {{HbO}_{2} + {Hb}} \right)}*100\%}} & \left( {{Eqn}.\mspace{11mu} 1} \right)\end{matrix}$

where HbO₂ refers to oxygenated hemoglobin (i.e., “oxyhemoglobin”) andHb refers to deoxygenated hemoglobin (i.e., “deoxyhemoglobin”). In thearterial circulatory system under normal conditions, there is a highproportion of HbO₂ to Hb, resulting in an arterial oxygen saturation(defined as SaO₂%) of 95-100%. After delivery of oxygen to tissue viathe capillaries, the proportion of HbO₂ to Hb decreases. Therefore, themeasured oxygen saturation of venous blood (defined as SvO₂%) is lowerand may be about 70%.

One spectrophotometric method, called pulse oximetry, determinesarterial oxygen saturation (SaO₂) of peripheral tissue (i.e. finger,ear, nose) by monitoring pulsatile optical attenuation changes ofdetected light induced by pulsatile arterial blood volume changes in thearteriolar vascular system. The method of pulse oximetry requirespulsatile blood volume changes in order to make a measurement. Sincevenous blood is not pulsatile, pulse oximetry cannot provide anyinformation about venous blood.

Near-infrared spectroscopy (NIRS) is an optical spectrophotometricmethod of continually monitoring tissue oxygenation that does notrequire pulsatile blood volume to calculate parameters of clinicalvalue. The NIRS method utilizes light in the near-infrared range (700 to1,000 nm) that can pass easily through skin, bone and other tissueswhere it encounters hemoglobin located mainly within micro-circulationpassages; e.g., capillaries, arterioles, and venuoles. Hemoglobinexposed to light in the near infra-red range has specific absorptionspectra that varies depending on its oxidation state; i.e.,oxyhemoglobin (HbO₂) and deoxyhemoglobin (Hb) each act as a distinctchromophore. By using light sources that transmit near-infrared light atspecific different wavelengths, and measuring changes in transmitted orreflected light attenuation, concentration changes of the oxyhemoglobin(HbO₂) and deoxyhemoglobin (Hb) can be monitored.

The apparatus used in NIRS analysis typically includes a plurality oflight sources, one or more light detectors for detecting reflected ortransmitted light, and a processor for processing signals that representthe light emanating from the light source and the light detected by thelight detector. Light sources such as light emitting diodes (LEDs) orlaser diodes that produce light emissions in the wavelength range of700-1000nm at an intensity below that which would damage the biologicaltissue being examined are typically used. A photodiode or other lightsource detector is used to detect light reflected from or passed throughthe tissue being examined. The processor takes the signals from thelight sources and the light detector and analyzes those signals in termsof their intensity and wave properties.

It is known that relative changes of the concentrations of HbO₂ and Hbcan be evaluated using apparatus similar to that described above,including a processor programmed to utilize a variant of theBeer-Lambert Law, which accounts for optical attenuation in a highlyscattering medium like biological tissue. The modified Beer-Lambert Lawcan be expressed as:

A _(λ)=−log(I/I _(o))₈₀=α₈₀ *=*C*d*B _(λ) +G   (Eqn. 2)

wherein “A_(λ)” represents the optical attenuation in tissue at aparticular wavelength λ (units: optical density or OD); “I_(o)”represents the incident light intensity (units: W/cm²); “I” representsthe detected light intensity; “α_(λ)” represents the wavelengthdependent absorption coefficient of the chromophore (units: OD * cm⁻¹*μM⁻¹); “C” represents the concentration of chromophore (units: μM); “d”represents the light source to detector (optode) separation distance(units: cm); “B_(λ)” represents the wavelength dependent lightscattering differential pathlength factor (unitless); and “G” representslight attenuation due to scattering within tissue (units: OD). Theproduct of “d*B_(λ)” represents the effective pathlength of photontraveling through the tissue.

Absolute measurement of chromophore concentration (C) is very difficultbecause G is unknown or difficult to ascertain. However, over areasonable measuring period of several hours to days, G can beconsidered to remain constant, thereby allowing for the measurement ofrelative changes of chromophore from a zero-reference baseline. Thus, iftime t i marks the start of an optical measurement (i.e., a base line)and time t₂ is an arbitrary point in time after t₁, a change inattenuation (ΔA) between t i and t₂ can be calculated, and variables Gand I_(o) will cancel out providing that they remain constant.

The change in chromophore concentration (ΔC=C(t₂)−C(t₁)) can bedetermined from the change in attenuation ΔA, for example using thefollowing equation derived from the modified Beer-Lambert Law:

ΔA _(λ)=−log(I _(t2) |I _(t1))_(λ)=α_(λ) * ΔC*d*B _(λ)  (Eqn. 3)

Presently known NIRS algorithms that are designed to calculate therelative change in concentration of more than one chromophore use amultivariate form of Equation 2 or 3. To distinguish between, and tocompute relative concentration changes in, oxyhemoglobin (ΔHbO₂) anddeoxyhemoglobin (ΔHb), a minimum of two different wavelengths aretypically used. The concentration of the HbO₂ and Hb within the examinedtissue is determined in p,moles per liter of tissue (μM).

The above-described NIRS approach to determining oxygenation levels isuseful, but it is limited in that it only provides information regardinga change in the level of oxygenation within the tissue. It does notprovide a means for determining the absolute value of oxygen saturationwithin the biological tissue.

At present, information regarding the relative contributions of venousand arterial blood within tissue examined by NIRS is either arbitrarilychosen or is determined by invasive sampling of the blood as a processindependent from the NIRS examination. For example, it has beenestimated that NIRS examined brain tissue comprising about 60 to 80%blood venous and about 20 to 40% arterial blood. Blood samples fromcatheters placed in venous drainage sites such as the internal jugularvein, jugular bulb, or sagittal sinus have been used to evaluate NIRSmeasurements. Results from animal studies have shown that NIRSinterrogated tissue consists of a mixed vascular bed with avenous-to-arterial ratio of about 2:1 as determined from multiple linearregression analysis of sagittal sinus oxygen saturation (SssO₂) andarterial oxygen saturation (SaO₂). An expression representing the mixedvenous/arterial oxygen saturation (SmvO₂) in NIRS examined tissue isshown by the equation:

SmvO ₂ =Kv*SvO ₂ +Ka*SaO ₂   (Eqn. 4)

where “SvO₂” represents venous oxygen saturation; “SaO₂” representsarterial oxygen saturation; and Kv and Ka are the weighted venous andarterial contributions respectively, with Kv+Ka=1. The parameters Kv andKa may have constant values, or they may be a function of SvO₂ and SaO₂.Determined oxygen saturation from the internal jugular vein (SijvO₂),jugular bulb (SjbO₂), or sagittal sinus (SssO₂) can be used to representSvO₂. Therefore, the value of each term in Equation 4 is empiricallydetermined, typically by discretely sampling or continuously monitoringand subsequently evaluating patient arterial and venous blood fromtissue that the NIRS sensor is examining, and using regression analysisto determine the relative contributions of venous and arterial bloodindependent of the NIRS examination.

Some medical procedures involve limiting or completely stopping the flowof blood to an organ. For example, some procedures involve isolating theheart from the rest of the body by means of a cross clamp on the aortaand then cold cardioplegia is given into the heart through the aorticroot. The cold fluid (usually in the range of about 4-10° C.) ensuresthat the heart cools down to an approximate temperature of around 15-20°C. thus slowing down the metabolism of the heart and thereby preventingdamage to the heart muscle. The process may be further augmented by acardioplegic component which is high in potassium and magnesium. Thepotassium helps by arresting the heart in diastole thus ensuring thatthe heart does not use up the valuable energy stores during this periodof heart isolation. Blood can be added to this solution especially forlong procedures requiring more than half an hour of ascending aortacross-clamp time. Blood acts as a buffer and also supplies nutrients tothe heart during ischemia. Once the procedure on the heart vessels(e.g., coronary artery bypass grafting, or heart valve replacement, orcorrection of congenital heart defect, etc.) is over, the cross-clamp isremoved and the isolation of the heart is terminated so that normalblood supply to the heart is restored and the heart starts beatingagain.

During the isolation period, it would be of great value to monitor theoxygen saturation level of the heart to ensure that the heart has asufficient oxygen level to avoid damage.

The cessation of blood flow to an organ is not limited to hearts,however. For example, livers and kidneys are often removed from a donorfor transplant into a recipient. In such cases, there would be value inknowing the oxygen saturation level in the organ before, during, andafter the transplant.

What is needed, therefore, is a method for non-invasively determiningthe level of oxygen saturation within biological tissue that candetermine the absolute oxygen saturation value rather than a change inlevel, and one that can be used to directly determine the oxygensaturation levels of a body organ.

DISCLOSURE OF THE INVENTION

According to an aspect of the present invention, a method and apparatusfor non-invasively determining a blood oxygen saturation level within anorgan of a subject using direct application of a near infraredspectrophotometric sensor is provided. The method includes the steps of:a) transmitting a light signal directly into the subject's organ usingthe sensor along multiple wavelengths; b) sensing a first intensity ofthe light signal and a second intensity of the light signal, after thelight signal travels a predetermined distance through the organ of thesubject; c) determining an attenuation of the light signal alongmultiple third wavelengths using the sensed first intensity and sensedsecond intensity of wavelengths; d) determining a difference inattenuation of the light signal between multiple wavelengths; and e)determining the blood oxygen saturation level within the subject's organusing the difference in attenuation between the multiple wavelengths.

According to another aspect of the present invention, an apparatus fornon-invasively determining a blood oxygen saturation level within anorgan of a subject is provided. The apparatus includes at least one nearinfrared spectrophotometric sensor operable to be placed in contact withthe organ, and a processor. The sensor has at least one light source andat least one light detector. The light source is operable to transmit alight signal that includes a first wavelength, a second wavelength, anda third wavelength. The light detector is operable to sense the lightsignal along the first, second, and third wavelengths after the lightsignal travels a predetermined distance through the organ tissue. Thesensor is operable to produce data signals representative of the sensedlight signal. The processor is adapted to receive the data signals fromthe sensor, and is adapted to determine an attenuation of the lightsignal for each of the first, second, and third wavelengths. Theprocessor is further adapted to determine the blood oxygen saturationlevel within the organ tissue using the difference in attenuation.

According to another aspect of the present invention, a method forregulating a tissue oxygenation level within a mammalian organ isprovided. The method includes the steps of: a) providing an organ tissueoxygenation level threshold; b) applying a near infraredspectrophotometric sensor onto a region of the organ, which sensor is incommunication with a processor adapted to receive data signals from thesensor, and is adapted to determine the oxygen saturation level withinthe organ tissue using the data signals; c) sensing the oxygensaturation level within the organ tissue using the spectrophotometricsensor, and producing a sensed organ tissue oxygenation level valueusing the processor; d) comparing the organ tissue oxygenation levelthreshold and the sensed organ tissue oxygenation level value; and e)selectively treating the organ to increase the tissue oxygenation levelwithin the organ based on the comparison.

According to another aspect of the present invention, a method formonitoring the effects of cardioplegia administered to a heart isprovided. The method includes the steps of: a) applying a near infraredspectrophotometric sensor onto a region of the heart, which sensor is incommunication with a processor adapted to receive data signals from thesensor, and is adapted to determine the oxygen saturation level withinheart tissue using the data signals; b) sensing the oxygen saturationlevel within the heart tissue using the spectrophotometric sensor beforean administration of a cardioplegia to the heart, and producing apre-administration sensed heart tissue oxygenation level value using theprocessor; c) administering a cardioplegia to the heart; and d) sensingthe oxygen saturation level within the heart tissue using thespectrophotometric sensor after the administration of the cardioplegiato the heart, and producing a post-administration sensed heart tissueoxygenation level value using the processor.

These and other objects, features, and advantages of the presentinvention method and apparatus will become apparent in light of thedetailed description of the invention provided below and theaccompanying drawings. The methodology and apparatus described belowconstitute a preferred embodiment of the underlying invention and donot, therefore, constitute all aspects of the invention that will or maybecome apparent by one of skill in the art after consideration of theinvention disclosed overall herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagrammatic side representation of a NIRS sensor disposedon the surface of an organ.

FIG. 2 is a diagrammatic planar view of a NIRS sensor.

FIG. 3 is a diagrammatic representation of a NIRS system, including asensor placed on an organ of a subject.

FIG. 4 is a block diagram of the present methodology.

FIG. 5 is a graph showing an exemplary plot of absorption coefficientvs. wavelength.

FIG. 6 graphically illustrates case study data in the form of StO₂ valueversus time.

FIG. 7 is a graphical illustration depicting TUT and AUT regions.

DETAILED DESCRIPTION THE INVENTION

The present method of and apparatus for non-invasively determining theblood oxygen saturation level within a subject's tissue is provided thatutilizes a near infrared spectrophotometric (NIRS) sensor that includesa transducer capable of transmitting a light signal into the tissue of asubject and sensing the light signal once it has passed through thetissue via transmittance or reflectance. The present method andapparatus can be used with a variety of NIRS sensors. The present methodis not limited to use with this preferred NIRS sensor, however.

Referring to FIGS. 1-5, the preferred NIRS sensor includes a transducerportion 10 and processor portion 12. The transducer portion 10 includesan assembly housing 14 and a connector housing 16. The assembly housing14, which is a flexible structure that can be attached directly to asubject's body, includes one or more light sources 18 and one or morelight detectors 19, 20. A sterile disposable envelope or pad may be usedto mount the assembly housing 14 to the subject's skin or organ. Lightsignals of known but different wavelengths from the light sources 18emit through a prism assembly 22. The light sources 18 are preferablylaser diodes that emit light at a narrow spectral bandwidth atpredetermined wavelengths. Alternative light emitting diodes (LEDs) canbe used if the algorithm is drafted to consider the LEDs characteristicbroad spectral bandwidth emitted light. In one embodiment, the laserdiodes are mounted within the connector housing 16. The laser diodes areoptically interfaced with a fiber optic light guide to the prismassembly 22 that is disposed within the assembly housing 14. In a secondembodiment, the light sources 18 are mounted within the assembly housing14. A first connector cable 26 connects the assembly housing 14 to theconnector housing 16 and a second connector cable 28 connects theconnector housing 16 to the processor portion 12. The light detectors19, 20 each include one or more photodiodes, which are operablyconnected to the processor portion 12 via the first and second connectorcables 26, 28. The processor portion 12 includes a processor forprocessing light intensity signals from the light sources 18 and one orboth light detectors 19, 20.

The processor 12 includes a central processing unit (CPU) and is adapted(e.g., programmed) to selectively perform the functions necessary toperform the present method. It should be noted that the functionality ofprocessor 12 may be implemented using hardware, software, firmware, or acombination thereof. A person skilled in the art would be able toprogram the processor 12 to perform the functionality described hereinwithout undue experimentation. The processor 12 utilizes an algorithmthat characterizes a change in attenuation as a function of thedifference in attenuation between different wavelengths. In someembodiments, the present method accounts for but minimizes the effectsof pathlength and parameter “E”, that latter of which represents energylosses (i.e. light attenuation) due to light scattering within tissue(G), other background absorption losses from biological compounds (F),and other unknown losses including measuring apparatus variability (N).E=G+F+N. Multi-tissue layer organs such as the kidney benefit frommulti-detector NIRS sensors and algorithms In some embodiments, analternative algorithm may be used that considers fewer or differentenergy loss components; e.g., if a subject heart is being directlysensed for oxygen saturation, an alternative algorithm may be used thatrecognizes the absence of certain types of tissue (e.g., skin, bone,etc.) and the signal energy losses associated therewith.

Refer to FIG. 1, the absorption Abx detected from the deep lightdetector 20 comprises of attenuation and energy loss from both the deepand shallow tissue, while the absorption A_(xλ)detected from the shallowlight detector 19 comprises of attenuation and energy loss from shallowtissue only. Absorptions A_(bλ)and A_(xλ)can be expressed in the form ofEquation 5 and Equation 6 below which is a modified version of Equation2 that accounts for energy losses due to “E”:

A _(bλ)=−log(I _(b) |I _(o))_(λ)=α_(λ) *C _(b) *L _(b)+α_(λ) *C _(x) *L_(x) +E _(λ)  (Eqn. 5)

A _(bλ)=−log(I _(b) |I _(o))_(λ)=α_(λ) *C _(x) *L _(x)+E_(xλ)  (Eqn. 6)

As indicated above, in some applications (e.g., direct organ sensing,where the signal does not traverse skin or bone) it may be possible tosense using a sensor with a single detector. In those instances, thefollowing equation can used to represent absorption:

A _(bλ)=−log(I _(b) |I _(o))_(λ)=α_(λ) *C _(b) *L _(b)+E_(λ)  (Eqn. 7)

Substituting Equation 6 into Equation 5 yields A′_(λ), which representsattenuation and energy loss from deep tissue only:

$\begin{matrix}{A_{\lambda}^{\prime} = {{A_{b\; \lambda} - A_{x\; \lambda}} = {{{\alpha_{\lambda}*C_{b}*L_{b}} + \left( {E_{\lambda} - E_{x\; \lambda}} \right)} = {- {\log \left( \frac{I_{b}}{I_{x}} \right)}_{\lambda}}}}} & \left( {{Eqn}.\mspace{11mu} 8} \right)\end{matrix}$

Where L is the effective pathlength of the photon traveling through thedeep tissue and A′₁ and A′₂, are the absorptions of two differentwavelengths. Let E′_(λ)=E_(λ)−E_(xλ), therefore:

A′ ₁ −A′ ₂ =ΔA′ ₁₂   (Eqn. 9)

Substituting Equation 7 or 8 into Equation 9 for A′₁ and A′₂, ΔA′₁₂ canbe expressed as:

ΔA′ ₁₂=α_(λ12) *C _(b) *L _(b) +ΔE′ ₁₂   (Eqn. 10)

and rewritten Equation 10 in expanded form:

$\begin{matrix}{{\Delta \; A_{12}^{\prime}} = {{{{\langle{{\left( {\alpha_{r\; 1} - \alpha_{r\; 2}} \right)\lbrack{Hb}\rbrack}_{b} + {\left( {\alpha_{o\; 1} - \alpha_{o\; 2}} \right)\left\lbrack {HbO}_{2} \right\rbrack}_{b}}\rangle}L_{b}} + \left( {E_{1}^{\prime} - E_{2}^{\prime}} \right)} = {\left( {{\Delta\alpha}_{r\; 12}*\lbrack{Hb}\rbrack_{b}*L_{b}} \right) + \left( {\Delta \; \alpha_{o\; 12}*\left\lbrack {HbO}_{2} \right\rbrack_{b}*L_{b}} \right) + {\Delta \; E_{12}^{\prime}}}}} & \left( {{Eqn}.\mspace{11mu} 11} \right)\end{matrix}$

where:

(Δα_(r12)*[Hb]_(b)* L_(b)) represents the attenuation attributable toHb;

(Δα_(b12)*[HbO₂]_(b)* L_(b)) represents the attenuation attributable toHbO₂; and

ΔE′₁₂ represents energy losses (i.e. light attenuation) due to lightscattering within tissue, other background absorption losses frombiological compounds, and other unknown losses including measuringapparatus variability. As indicated above, the specific energy lossesaccounted for can be varied to suit the application at hand; e.g.,inclusion or exclusion of energy losses attributable to skin and bone,use of a single detector versus a pair of detectors, etc.

The multivariate form of Equation 10 is used to determine [HbO₂]_(b) and[Hb]_(b) with three different wavelengths:

$\begin{matrix}{{\left\lfloor \begin{matrix}{{\Delta \; A_{12}^{\prime}} - {\Delta \; E_{12}^{\prime}}} \\{{\Delta \; A_{13}^{\prime}} - {\Delta \; E_{13}^{\prime}}}\end{matrix} \right\rfloor \left( L_{b} \right)^{- 1}} = {\left\lfloor \begin{matrix}{\Delta\alpha}_{r\; 12} & {\Delta\alpha}_{o\; 12} \\{\Delta\alpha}_{r\; 13} & {\Delta \; \alpha_{o\; 13}}\end{matrix} \right\rfloor \left\lfloor \begin{matrix}\lbrack{Hb}\rbrack_{b} \\\left\lbrack {HbO}_{2} \right\rbrack_{b}\end{matrix} \right\rfloor}} & \left( {{Eqn}.\mspace{11mu} 12} \right)\end{matrix}$

Rearranging and solving for [HbO₂]_(b) and [Hb]_(b), simplifying the Δαmatrix into [Δα′]:

$\begin{matrix}{{{{\begin{bmatrix}{\Delta \; A_{12}^{\prime}} \\{\Delta \; A_{13}^{\prime}}\end{bmatrix}\left\lbrack {\Delta\alpha}^{\prime} \right\rbrack}^{- 1}\left( L_{b} \right)^{- 1}} - {{\begin{bmatrix}{\Delta \; E_{12}^{\prime}} \\{\Delta \; E_{13}^{\prime}}\end{bmatrix}\left\lbrack {\Delta\alpha}^{\prime} \right\rbrack}^{- 1}\left( L_{b} \right)^{- 1}}} = \begin{bmatrix}\lbrack{Hb}\rbrack_{b} \\\left\lbrack {HbO}_{2} \right\rbrack_{b}\end{bmatrix}} & \left( {{Eqn}.\mspace{11mu} 13} \right)\end{matrix}$

Then combined matrices [ΔA′] [Δα′]⁻¹=[A_(c)] and [ΔE] [Δα′]⁻¹=[Ψ_(c)]:

$\begin{matrix}{{{\left\lfloor \begin{matrix}A_{Hb} \\A_{{HbO}_{2}}\end{matrix} \right\rfloor \left( L_{b} \right)^{- 1}} - {\left\lfloor \begin{matrix}\Psi_{Hb} \\\Psi_{{HbO}_{2}}\end{matrix} \right\rfloor \left( L_{b} \right)^{- 1}}} = \left\lfloor \begin{matrix}\lbrack{Hb}\rbrack_{b} \\\left\lbrack {HbO}_{2} \right\rbrack_{b}\end{matrix} \right\rfloor} & \left( {{Eqn}.\mspace{11mu} 14} \right)\end{matrix}$

The parameters A_(IIb) and A_(IIbO2) represent the product of thematrices [ΔA_(λ)] and [Δα′]⁻¹ and the parameters Ψ_(Hb) and Ψ_(HbO2)represent the product of the matrices [ΔE′_(λ)] and λ[Δα′]⁻¹. Todetermine the level of organ blood oxygen saturation (StO₂), Equation 14is rearranged using the form of Equation 1 and is expressed as follows:

$\begin{matrix}{{{SnO}_{2}\mspace{14mu} \%} = {\frac{\left( {A_{{HbO}_{2}} - \Psi_{{HbO}_{2}}} \right)}{\left( {A_{{HbO}_{2}} - \Psi_{{HbO}_{2}} + A_{Hb} - \Psi_{Hb}} \right)}*100\%}} & \left( {{Eqn}.\mspace{11mu} 15} \right)\end{matrix}$

Note that the effective pathlength L_(b) cancels out in the manipulationfrom Equation 14 to Equation 15.

The value for StO₂ is initially determined from SmvO₂ using Equation 4and the empirically determined values for SvO₂ and SaO₂, determined fromthe organ to be monitored. The empirically determined values for SvO₂and SaO₂ are based on data developed by discrete sampling (e.g.,collections of blood sample at discrete points in time) or continuousmonitoring (e.g., sensing blood flow through a catheter) of thesubject's blood from the arterial input and venous output of the organto be monitored, performed at or about the same time as the sensing ofthe organ tissue with the sensor. The temporal and physical proximity ofthe NIRS sensing and the development of the empirical data helps assureaccuracy. For example, in calibrating the NIRS sensor to the heart, SaO₂can be determined from blood in the aorta (arterial blood enters tocoronary arties of the heart via the aorta) or any systemic artery.Heart SvO₂ will be determined from blood drawn from the coronary venousdrainage of the heart. The initial values for Kv and Ka within Equation4 are clinically reasonable values for the circumstances at hand.Alternatively, only SvO₂ may be used for empirical calibration (i.e.,Ka=0, Kv=1). The values for A_(HbO2) and A_(Hb) are determinedmathematically using the values for I_(xλ)and I_(xλ)for each wavelengthsensed with the NIRS sensor (e.g., using Equation 5 and 6). Thecalibration parameters Ψ_(Hb) and Ψ_(HbO2), which account for energylosses due to scattering as well as other background absorption frombiological compounds, are then determined using Equation 14 andnon-linear regression techniques by correlation to different weightedvalues of SvO₂ and SaO₂; i.e., different values of Ka and Kv.Statistically acceptable values of Kv and Ka and Ψ_(Hb) and Ψ_(HbO2) areconverged upon using the non-linear regression techniques. Experimentalfindings show that after proper selection of Ka and Kv, the calibrationparameters Ψ_(Hb) and Ψ_(HbO2) are constant within a statisticallyacceptable margin of error for an individual NIRS sensor used to monitordirect organ oxygenation on different human subjects. In other words,once the sensor is calibrated it can be used on various human subjectsand produce accurate information for each human subject for each organtype. The same is true for animal subjects.

In the determination of the StO₂ percentage, the effective photonpathlength L_(b) cancels out. If, however, the photon pathlength isknown or estimated, then the determination of the total value of Hband/or HbO₂ is possible. For example, if a value for pathlength L_(b) isinput into Equation 14 along with the calibration values Ψ_(Hb) andΨ_(HbO2), then the total value of Hb and/or HbO₂ can be calculated.According to Equation 2, pathlength L can be estimated from the productof “B*d”. The light source to detector separation (optode) distanceparameter “d” in the pathlength calculation is a measurable value andcan be made constant by setting a fixed distance between light source todetector in the NIRS sensor design. Alternatively, the parameter “d” canbe measured once the optodes are placed on the subject by use ofcalipers, ruler, or other distance measurement means. The pathlengthdifferential factor “B” is more difficult to measure and requires moresophisticated equipment. An estimation of the value of “B” can bedetermined within a statistically acceptable margin of error forempirical data collected from subjects; e.g., a large data set ofmeasured organ differential pathlength factor values. Substitution ofthese predetermined values of “B” into Equation 14 results in thedetermination of the total values of Hb and HbO₂.

After the calibration parameters Ψ_(Hb) and Ψ_(HbO2) are determinedusing the above-described methodology for an individual NIRS sensor,this particular sensor is said to be calibrated. A calibrated NIRSsensor affords accurate measurement of total tissue oxygen saturation,StO₂, by non-invasive means for each particular organ type. Thecalibrated sensor can be used thereafter on any human patient, includingadults and neonates. The same is true for an animal subject if thesensor was calibrated on animals.

Besides Hb and HbO₂, other biological constituents of interest (e.g.,cytochrome aa₃, etc.) could be determined using the multivariate formsof equations 2, 3, 6 or 7. For each additional constituent to bedetermined, an additional measuring wavelength will be needed.

In an alternative embodiment, the above-described methodology can becombined with pulse oximetry techniques to provide an alternativenon-invasive method of distinguishing between oxygen saturationattributable to venous blood and that attributable to arterial blood. Asdemonstrated by Equation 4, SmvO₂ is determined by the ratio of venousoxygen saturation SvO₂ and arterial oxygen saturation SaO₂ from eachparticular organ type. A calibrated NIRS sensor affords accuratemeasurement of total tissue oxygen saturation, StO₂, by using regressiontechniques by correlation to mixed venous oxygen saturation SmvO₂.Therefore, the following expression will result:

StO₂=SmvO₂=K_(v)*SvO₂+Ka*SaO₂   (Eqn. 16)

Non-invasive pulse oximetry techniques can be used to determine thearterial oxygen saturation (SaO₂) of peripheral tissue (i.e. finger,ear, nose) by monitoring pulsatile optical attenuation changes ofdetected light induced by pulsatile arterial blood volume changes in thearteriolar vascular system. Arterial blood oxygen saturation determinedby pulse oximetry is clinically denoted as SpO₂. If NIRS monitoring andpulse oximetry monitoring are done simultaneously and SpO₂ is set equalto SaO₂ in Equation 16, then venous oxygen saturation of a particularorgan being monitored can be determined from the following expression:

$\begin{matrix}{{SvO}_{2} = \frac{{StO}_{2} - \left( {{Ka}*{SpO}_{2}} \right)}{Kv}} & \left( {{Eqn}.\mspace{11mu} 17} \right)\end{matrix}$

For the heart, venous oxygen saturation SvO₂ would be determined fromthe coronary drainage SvO2 and the parameters Ka and Kv would beempirically determined during the calibration of the NIRS sensor. Undermost physiological conditions, SpO₂ is representative of organ arterialoxygen saturation SaO₂. Therefore, depending on which venous saturationparameter was used to calibrate the NIRS sensor, this clinicallyimportant parameter (organ venous oxygen saturation) can be determinedby Equation 23 by non-invasive means.

To perform a corrective procedure (e.g., coronary artery bypassgrafting, or heart valve replacement, or correction of congenital heartdefect, etc.) on a subject's heart, it is often necessary to arrest orstop the subject's heart so that surgical procedures can be done in astill and bloodless field. In some instances this is achieved bydiverting deoxygenated blood that would otherwise entering the heartinto a heart-lung machine. The heart-lung machine takes over thefunction of the lung by oxygenating the blood and removing carbondioxide. After oxygenation, filtration and removal of carbon dioxide,the machine pumps the blood back into the body usually through theaorta.

At the same time, the subject's heart is isolated, for example, using anaortic cross-clamp on the distal aorta. Cold cardioplegia issubsequently given into the heart through the aortic root. The coldfluid (usually in the range of about 4-10° C.) ensures that the heartcools down to an approximate temperature of around 15-20° C. thusslowing down the metabolism of the heart and thereby preventing damageto the heart muscle. The process may be further augmented by acardioplegic component which is high in potassium and magnesium. Thepotassium helps by arresting the heart in diastole thus ensuring thatthe heart does not use up the valuable energy stores during this periodof heart isolation. Blood can be added to this solution especially forlong procedures requiring more than half an hour of cross-clamp time.Blood acts a buffer and also supplies nutrients to the heart duringischemia.

During the procedure (e.g., before, during, and after isolation), asterile NIRS sensor is placed on a region of the heart. The sensor mayhave one or more detectors. The sensor is operated to transmit lightsignals into the heart tissue and receive light signals that have passedthrough the heart tissue. The oxygen saturation of the heart tissue isdetermined using the oximeter described above.

Using the present invention oximeter in the way described (or similarway) enables the physician to monitor the oxygen saturation level of theheart tissue and take corrective action (e.g., add a cardioplegiccomponent) if the saturation reaches a predetermined level. The abilityto place a sensor directly in contact with the heart during theprocedure enhances the accuracy of the data, as there is no interferingtissue overlaying the heart, thereby providing the care giver withquick, concise information relation to the oxygenation state of theorgan. In this manner, the operator can monitor in real-time thecardioplegia of the heart, including the rate of recovery from thecardioplegia.

Once the procedure on the heart (e.g., coronary artery bypass grafting,or heart valve replacement, or correction of congenital heart defect,etc.) is over, the cross-clamp is removed and the isolation of the heartis terminated so that normal blood supply to the heart is restored andthe heart starts beating again. At this point, the oximeter can be usedto confirm the oxygen saturation level within the heart tissue is withinacceptable limits.

The utility of the present invention can be seen through the case studydepicted in FIG. 6, which shows a recording of StO₂ from a present NIRSsensor placed directly on the heart of a pig. The events occurringduring the study are identified to illustrate the relationship between achange in the level of StO₂ and the event encountered during the cardiacsurgery. Event 1 (“E1”) shows normal sinus rhythm. The StO₂ value forEvent 1 is fairly low due to the high oxygen extraction of the heartmuscle. Blood drawn from the venous return of the heart (carotid sinus)is typically highly oxygen de-saturated, with an oxygen saturation valuearound 40%. During Event 2 (“E2”), the pig was put on a cardiac bypasspump. During Event 3 (“E3”), a cross clamp was placed on the ascendingaorta, proximal to the cardiopulmonary bypass (“CPB”) inflow cannula.The cross clamp stopped blood flow to the heart; e.g., to allow aphysician to perform surgery on the heart devoid of blood in the field.As a result, the StO₂ value decreased because the heart was no longerreceiving oxygenated blood. Removal of the cross-clamp resulted in aresumption of blood perfusion to the heart, and the StO₂ valueconsequently increased back to pre-clamping StO₂ levels. Event 4 (“E4”)was a repeat of Event 3. During Event 5 (“E5”), the cross-clamp wasapplied again, with a consequent decrease in the StO₂ level.Subsequently, cardioplegia was injected into the ascending aorta. Thecardioplegia consisted of cooled (10 degrees C.) arterial blood and asaline-like solution, that included a relatively high level of potassiumand other components such as adenin and Sodium (Na) channel blockerssolution. The only vessels that extend out from the ascending aorta arethe coronaries, provided that the aortic valve is competent. Theinfusion of cardioplegia into the ascending aorta passed through thecoronary arteries. Since arterial blood is nearly 100% oxygenated, thecardiac NIRS sensor sensed a sharp rise in StO₂ level as the highlyoxygenated blood perfused through the coronary vessels of the heart. TheStO₂ level remained elevated for a few minutes as the heart musclemetabolizes the oxygen from the injected blood solution. Eventually all(or nearly all) the oxygen was extracted from the injected bloodsolution, causing the StO₂ level to decrease steadily until a value nearzero was approached, which is depicted at Event 6 (“E6”). The StO₂ levelremained near zero until a second dose of cardioplegia wasadministered—depicted at Event 7 (“E7”). The StO₂ level subsequentlyrose again to elevated values as the heart received freshly oxygenatedblood solution from the second dose of cardioplegia. As the second doseof cardioplegia wore off, the StO₂ level decreased. This form ofcardioplegia is referred to as antegrade cardioplegia. Another type ofcardioplegia is called retrograde cardioplegia, which is injected intothe coronary sinus of the heart to induce the same effect.

At Event 8 (“E8”), the cross-clamp was removed and the heart reperfusedfrom systemic flow from the ascending aorta. At Event 9 (“E9”), theheart underwent ventricular fibrillation and arrhythmia Because theheart's contraction was uncoordinated and the cardiac muscles were notfully contracting, the oxygen consumption was reduced, resulting in ahigher than normal cardiac StO₂ level. At Event 10 (“E10”), the heartwas defibrillated to induce normal sinus rhythm, at which point the StO₂level returned to a normal sinus rhythm value. Event 11 (“E11”)illustrates a potential problem from blood pooling around the heart. Thepooled blood negatively affected the ability of the NIRS sensor toaccurately sense the StO₂ level within the heart. A NIRS cardiac sensorthat is well adhered to the heart muscle can avoid this problem becauseit prevents outside blood leaking into the sensor's optical interfacewith the heart muscle. In one embodiment, the sensor can include amechanism for inducing suction between the sensor and the surface of theheart; e.g., a syringe positioned to create suction can be used tocreate and maintain a seal that prevents outside blood leakage. At Event12 (“E12”), the animal expired and the StO₂ level decreased to near zerovalues.

It can be seen from the above that the present apparatus for, and methodof, directly monitoring the level of StO₂ in an organ using an NIRSsensor, provides an accurate and effective tool for directly monitoringboth the StO₂ level of the organ and the affects of cardioplegia on theStO₂ level. Furthermore, the present invention provides the ability toregulate the StO₂ level within the organ using information collectedduring such monitoring. For example, the StO₂ level within a subject'sheart can be directly monitored using the present invention during organsurgery (e.g., heart surgery). In one embodiment, the level of StO₂ ismonitored and if the StO₂ level decreases beyond a predetermined minimumvalue threshold while the heart is cross-clamped, a predetermined dosageof cardioplegia is injected into the organ to cause the StO₂ level toincrease above the threshold. It should be noted that the StO₂ thresholdmay be chosen based on the circumstances of the application; e.g., thethreshold may be a value recorded during normal sinus rhythm and cardiacfunction, or some other clinically relevant value.

In another embodiment, the StO₂ level is again monitored and the valueof the StO₂ level is compared against a predetermined StO₂ levelthreshold as a function of time. For example, if the StO₂ level withinthe organ drops below the StO₂ threshold (referred to as an “event”),the amount of time that the StO₂ value is below the threshold (i.e., theduration of the event) is recorded and summed to create a time underthreshold (i.e., “TUT”) value (typically expressed in units of secondsor minutes). FIG. 7 graphically illustrates a TUT region. Anytime theStO₂ level exceeds the threshold, the TUT value remains constant andunchanged. The TUT value can then be compared to a threshold value forsupplementary and/or corrective action if required.

The monitoring and collective summing relative to StO₂ values below thethreshold can also be implemented (e.g., within the processor 12)graphically using a graph of StO₂ (e.g., Y-axis) versus time (e.g.,X-axis). For example, if the comparison of the sensed StO₂ level withthe predetermined StO₂ level reveals that the StO₂ level within theorgan is below the threshold value, the area of the graph defined by thedata line and the threshold value (i.e., from start of the event to thefinish of the event) is calculated and summed to create an area underthreshold (i.e., “AUT”) value. FIG. 7 graphically illustrates an AUTregion. Anytime the StO₂ level exceeds the threshold, the AUT valueremains constant and unchanged. The AUT value can then be compared to athreshold value for supplementary action if required.

The area under StO₂ threshold (“AUT”) value can also be calculatedmathematically, where the AUT value (in units of StO₂%·time) is theaccumulated oxygen saturation deficit below a threshold multiplied bytime. AUT can be calculated, for example, using the following equation:

AUT=AUT _(past)+(StO _(2threshold) −StO _(2value))×sample rate   [Eqn.18]

where AUT is the collective value, AUT_(past) is the previous collectivevalue, StO₂ thresholds is the threshold value, and StO₂ value is thecurrently sensed StO₂ value. If the currently sensed StO₂ value is abovethe threshold, then the collective AUT value remains constant. The AUTis calculated for the entire procedure or just for one portion of theprocedure (e.g., during a period of circulatory arrest). Because theStO₂ level of an organ will likely fluctuate during the course of anoperation (i.e., StO₂ values above and below the predetermined thresholdvalue), the AUT value can be periodically determined. To illustrate,consider the following monitoring using an arbitrary sample rate ofsensing every five minutes and a StO₂ threshold value of 60): At a firstpoint in time (T1), the AUT value may be considered to be zero (e.g.,current sensing not yet started, and no past value of AUT). Five minuteslater at T2, the StO₂ of the organ is sensed and has a value of 58.Using Eqn. 1 above, the AUT value is calculated: [(0+(60−58)×5=10],because there is no AUT_(past) value, and it is therefore assigned avalue of zero. Five minutes later at T2, the StO2 of the organ is sensedand has a value of 57. Again using Eqn. 1: [((60-57)×5)+10=25], becausethe AUT_(past) value is equal to ten. Five minutes later at T3, the StO₂of the organ is sensed and has a value of 63. In this instance, becausethe sensed StO₂ value is greater than the threshold, the difference isassigned a value of zero, and the AUT value remains at twenty-five,because the AUT_(past) value is equal to twenty-five.

It should be noted that the AUT value is not a percentage of time spentunder a given threshold, but rather is an absolute value that can beused during or after the procedure as part of the subject's care; e.g.,depending upon the application, there may be little difference inclinical terms between a collective StO₂ duration of one hour underneatha threshold during a 10 hour case (10%) as opposed to a collective onehour during a one hour case (100%).

It can be seen from the description above, including the variousdifferent embodiments, that the present invention provides a method andapparatus for monitoring cardioplegia. The present invention can be usedto protect the subject's heart (or other organ), by alerting thephysician to take a proactive step (e.g., inject the next round ofcardioplegia) when certain predefined conditions are met. The presentmethod can be utilized in varying degrees of automation (e.g.,algorithmically within the processor 12), including an automatedcardioplegia device that includes structure adapted to automaticallyinject cardioplegia based on NIRS StO₂ monitoring input.

As indicated above, the present apparatus and method can be used todirectly monitor numerous organs within a subject's body and is not,therefore, limited to a cardiac application. For example, the presentinvention can be used to monitor oxygenation levels within a liver orkidney allograft before, during and after transplantation. Issues mayarise during transplantation such as reconnect of blood vessels thatfeed the organ, as well as preventing hyperoxygenation and reperfusioninjury. An NIRS organ sensor could be moved to different positions onthe organ to make sure each region or compartment is perfusedadequately. This is especially true with liver transplantation. Toprevent hyperoxygenation and in part, reperfusion injury, the organ StO₂can be controlled by observing the NIRS monitor StO₂ value and thenregulating blood flow or the oxygenation level so that StO₂ ismaintained within a predetermined range during transplant. Specifically,a sterile NIRS sensor is placed on a region of the liver or kidneyallograft. Secure attachment of the sensor can be made by suction meansor by suturing the sensor onto the organ. Alternatively, a loosewrapping over the sensor to hold it on the organ, such as a stretchablenet-like apparatus can be used. Although the sensor may have one or moredetectors, the direct sensing of the organ typically permits the use ofa single detector sensor since attenuation attributable to non-organtissue layers is avoided. The sensor is operated to transmit lightsignals into the liver tissue and receive light signals that have passedtherethrough. The oxygen saturation of the liver tissue is determinedusing the oximeter described above. As indicated above, the direct organmonitoring made possible using the present invention enables thephysician to accurately monitor the organ and take corrective action asneeded.

Since many changes and variations of the disclosed embodiment of theinvention may be made without departing from the inventive concept, itis not intended to limit the invention otherwise than as required by theappended claims.

What is claimed is:
 1. A method for non-invasively determining a bloodoxygen saturation level within tissue of an internal organ of a subject,comprising: applying a near infrared spectrophotometric sensor on anexternal surface of the internal organ, which sensor includes at leastone light source and at least one detector; operating the sensor to emitlight from the light source at an incident light intensity directly intothe tissue of the internal organ at a first tissue location, whichemitted light includes a plurality of wavelengths, and to sense saidemitted light at a second tissue location, separated from the firsttissue location, which emitted light has traveled through the tissuebetween the first tissue location and the second tissue location, and toproduce signals representative of the intensity of the sensed emittedlight; and using a processor to execute instructions stored in a memorydevice, which instructions cause the processor to: determine anattenuation value of the emitted light for each of the plurality ofwavelengths using a first value representative of the incident lightintensity for the respective wavelength and a second valuerepresentative of the intensity of the sensed emitted light for therespective wavelength; and determine a blood oxygen saturation level ofthe organ tissue using the determined attenuation values for each of theplurality of wavelengths.
 2. The method of claim 1, wherein the sensorapplied to the external surface of the organ is configured tointerrogate tissue contiguous with the external surface of the organ. 3.The method of claim 2, wherein the sensor has a plurality of lightdetectors.
 4. The method of claim 2, wherein the sensor is configured tobe applied to the external surface of a heart and to interrogate tissuecontiguous with the external surface of the heart.
 5. The method ofclaim 2, wherein the sensor is configured to be applied to the exteriorsurface of a liver and to interrogate tissue contiguous with theexternal surface of the liver.
 6. The method of claim 2, wherein thesensor is configured to be applied to the external surface of a kidneyand to interrogate tissue contiguous with the external surface of thekidney.
 7. The method of claim 1, wherein the at least one detector isspaced a distance apart from the light source, and wherein the distanceis such that the sensed emitted light travels substantially exclusivelythrough the organ tissue.
 8. The method of claim 1, wherein the at leastone detector includes a first detector spaced a first distance apartfrom the light source, and a second detector spaced a second distancefrom the light source, which second distance is greater than the firstdistance, and wherein the first and second distances are such that thesensed emitted light travels substantially exclusively through the organtissue.
 9. The method of claim 1, wherein the instructions stored in thememory device include a predetermined organ tissue oxygenation levelthreshold and which instructions further cause the processor to comparethe predetermined organ tissue oxygenation level threshold and thedetermined blood oxygen saturation level of the organ tissue.
 10. Anapparatus for non-invasively determining a blood oxygen saturation levelwithin tissue of an organ of a subject, comprising: a near infraredspectrophotometric sensor configured to be placed in contact with anexternal surface of the organ, which sensor has at least one lightsource and at least one light detector, which light source is operableto transmit a light signal at a plurality of wavelengths at an incidentlight intensity, and which light detector is operable to sense the lightsignal at each of the plurality of wavelengths after the light signaltravels a distance through the organ tissue, and produce data signalsrepresentative of an intensity of the sensed light signal at eachrespective wavelength; and a processor configured to receive the datasignals from the sensor, and configured to execute instructions storedin a memory device, which instructions cause the processor to: determinean attenuation value of the emitted light for each of the plurality ofwavelengths using a first value representative of the incident lightintensity for the respective wavelength and the signals representativeof the intensity of the sensed emitted light for the respectivewavelength; and determine a blood oxygen saturation level of the organtissue using the determined attenuation values for each of the pluralityof wavelengths.
 11. The apparatus of claim 10, wherein the sensor isconfigured to interrogate the organ tissue contiguous with the externalsurface of the organ where the sensor is placed in contact.
 12. Theapparatus of claim 11, wherein the sensor is configured to be applied tothe external surface of a heart and to interrogate tissue contiguouswith the external surface of the heart.
 13. The apparatus of claim 11,wherein the sensor is configured to be applied to the external surfaceof a liver and to interrogate tissue contiguous with the externalsurface of the liver.
 14. The apparatus of claim 11, wherein the sensoris configured to be applied to the external surface of a kidney and tointerrogate tissue contiguous with the external surface of the kidney.15. The apparatus of claim 10, wherein the at least one detector isspaced a distance apart from the light source, and wherein the distanceis such that the sensed emitted light travels substantially exclusivelythrough the organ tissue.
 16. The apparatus of claim 10, wherein the atleast one detector includes a first detector spaced a first distanceapart from the light source, and a second detector spaced a seconddistance from the light source, which second distance is greater thanthe first distance, and wherein the first and second distances are suchthat the sensed emitted light travels substantially exclusively throughthe organ tissue.